THE 


VEGETABLE  ALKALblDS. 


WITH  PARTICULAR  REFERENCE  TO  THEIR 
CHEMICAL  CONSTITUTION. 


BY 

DR.  AME  PICTET, 

Pro/cssor  in  the  Unimrsity  of  Geneva. 


FROM  THE  SECOND  FRENCH  EDITION. 


■ RENDERED  INTO  ENGLISH,  REVISED  AND  ENLARGED, 
WITH  THE  AUTHOR'S  SANCTION, 

BY 


H.  C.  BIDDLE,  Ph.D., 

Instructor  in  the  University  of  California. 


8vo,  vii  + 505  pages.  Cloth,  $5.00. 

Order  through  your  bookseller,  or  copies  will  be  forwarded  postpaid  by  the 
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NEW  YORK; 

JOHN  WILEY  & SONS. 
London;  CHAPMAN  & HALL,  Limited. 
1904. 


PREFACE. 


Since  the  appearance  in  1897  of  the  second  edition  of  Prof. 
Ame  Pictet’s  work,  La  Constitution  Chimique  des  Alcaloides 
Vegetaux,”  marked  advances  Lave  been  made  in  our  knowledge 
of  the  alkaloids.  ^ ^ 

The  chemistry  of  xanthine,  caffeine,  theobromine,  etc.,  has 
attained  a certain  completeness  of  development  in  the  recognition 
of  their  common  relation  to  purine  and  in  the  synthesis  of  the 
latter.  The  congtitudon  of  nicotine  has  been  established  by  its 
synthesis  and  three  new  alkaloids  have  been  isolated  from  the 
tobacco-plant  (Pictet).  Our  conceptions  regarding  the  jaborandi 
alkaloids  have  been  completely  revolutionized.  The  extensive  in- 
vestigations of  Ladenburg,  Merling,  and  Willstatter  have  been 
brought  to  a brilliant  conclusion  in  the  complete  synthesis  of 
atropine,  atropamine,  belladonnine,  inactive  cocaine,  and  tropa- 
cocaine.  Our  knowledge  regarding  the  constitution  of  morphine 
and  codeine  has  been  so  far  increased  that  probably  within  a 
short  time  the  synthesis  of  these  two  alkaloids  will  be  realized. 

These  advances  have  precluded  a simple  translation  of  the 
French  edition  and  have  necessitated  the  complete  rewriting  of 
several  chapters  and  the  revision  of  the  entire  work.  It  is  believed 
that  the  present  English  edition  fairly  sets  forth  the  latest  con- 
ceptions regarding  the  constitution  of  the  more  important  veg- 
etable alkaloids. 

It  may  be  noted  that  Prof.  Pictet’s  work  on  the  alkaloids  was 
rendered  into  German  in  1900  by  Wolffenstein  and  that  a Russian 
edition  is  in  process  of  preparation. 

H.  C.  Biddle. 

Berkeley,  Calif.,  Dec.  22,  1903. 

iii 


r^-T.'S 

prs- 

|pcww\ 


t 


’CONTENTS. 


• PAGE 

Introduction i 

FIRST  PART. 

ARTIFICIAL  BASES  CLOSELY  RELATED  TO  THE  NATURAL 

ALKALOIDS. 

I.  Pyridine . lo 

II.  Homolooues  oe  Pyridine 32 

A.  The  Picolinips 32 

B.  The  Lutidines 37 

C.  The  Collidines.  ...*.• 40 

Alcamines  of  the  Pyridine  Series 49 

III.  Carboxylic  Acids  OF  Pyridine.^ 55 

A.  The  Monocarboxylic  Acids  of  Pyridine 55 

B.  The  Dicarboxylic  Acids  of  Pyridine 61 

C.  The  Tricarboxylic  Acids  of  Pyridine 66 

D.  The  Tetracarboxylic  Acids  of  Pyridine . 72 

E.  Pyridine  Pentacarboxylic  Acid 73 

IV.  Dipyridyls 76 

V.,  Quinoline 79 

VI.  Methylquinolines.  .'. 89 

VII.  Phenylquinolines 96 

VIII.  Monocarboxylic  Acids  of  Quinoline 102 

IX.  Isoquinoline 107 

SECOND  PART. 

I THE  NATURAL  ALKALOIDS. 

X.  Distribution  and  General  Properties  of  the  Natural 

Alkaloids .’ . . . 114 

XL  Alkaloids  of  the  Hemlock 126 

XII.  PiPERINE 143 

XIII.  Trigonelline 149 

XIV.  Alkaloids  OF  THE  Betel-nut  Palm  (Areca  catechu) 152 

XV.  CiTRAZiNic  Acid 157 

• 

i p\ddi>i 


V 


VI 


CONTENTS. 


PAGE 

XVI.  The  Tobacco  Aekaeoids 159 

XVII.  The  Jaborandi  AivKaloids 17 1 

XVIII.  Cytisine  179 

XIX.  Sparteine 182 

XX.  The  Lupine  Alkaeoids 184 

XXI.  The  Solanum  Aekaloids 188 

XXII.  The  Coca  Aekaeoids 232 

XXIII.  The  Aekaloids  of  the  Pomegranate-tree 258 

XXIV.  The  Opium  Alkaeoids 264 

XXV.  Alkaloids  from  Hydrastis  canadensis 315 

XXVI.  Alkaloids  from  Corydalis  cava 331 

XXVII.  The  Cinchona  Alkaloids 337 

XXVIII.  The  Strychnos  Alkaloids 382 

XXIX.  Alkaloids  from  Peganum  harmala 395 

XXX.  Alkaloids  of  the  Aconite  Group 399 

XXXI.  The  Veratrum  Alkaloids 409 

XXXII.  Colchicine 417 

XXXIII.  The  Xanthine  Group 421 

XXXIV.  Allantoin 448 

XXXV.  The  Asparagine  Group 450 

XXXVI.  The  Choline  Group 470 

XXXVII.  The  Alkaloids  of  Mustard- seed 479 

XXXVIII.  Trimethylamine 484 

XXXIX.  Alkaloids  of  Unknown  Constitution 486 


THE  VEGETABLE  ALKALOIDS. 


INTRODUCTION. 

Taken  in  its  etymological  sense  the  word  alkaloids  may 
serve  to  designate  all  organic  substances  which  possess  basic 
properties;  some  authors,  indeed,  have  thus  used  the  term.  In 
general,  however,  its  application  is  limited  to  those  organic  bases 
which  are  formed  in  the  organism  of  the  plant.  A distinction 
is  in  this  way  drawn  between  basic  compounds  which  w'e  find 
in  nature  and  those  which  are  prepared  solely  in  the  laboratory. 
The  alkaloids,  then,  do  not  form  a well-defined  group  in  a rational 
classification  of  organic  compounds,  since  such  a classification 
would  be  based  on  chemical  constitution  and  not  upon  the  source 
from  which  they  were  derived. 

An  attempt  was  made  by  Konigs  in  1880  to  develop  a rational 
classification  of  the  bases  found  in  plants.  Investigations  on 
the  constitution  of  these  substances  showed  that,  if  not  all,  at  least 
a large  number  of  them  yielded  pyridine  as  the  ultimate  product 
of  their  decomposition.  It  was  natural,  then,  to  infer  that  they 
were  derivatives  of  this  base,  just  as  the  aromatic  compounds 
are  derivatives  of  benzol. 

Konigs  suggested  that  the  term  alkaloids  be  reserved  for 
those  natural  bases  which  are  pyridine  derivatives. 

The  proposal  at  first  met  the  hearty  approval  of  chemists; 
it  afforded  a strictly  scientific  classification  of  an  important  group 
of  organic  substances,  and  this  advantage  appeared  at  the  time 


2 


THE  VEGETABLE  ALKALOIDS. 


to  afford  compensation  for  the  necessity  of  excluding  from  the 
group  such  bases  as  caffeine,  choline,  betaine,  sinapine,  musca- 
rine, etc.,  which  do  not  contain  the  pyridine  nucleus. 

Through  later  numerous  and  important  investigations  on 
the  natural  bases,  however,  the  number  of  those  which  are  not 
derivatives  of  pyridine  has  been  greatly  increase  d ^lost  im- 
portant among  those  to  which  the  classification  of  Konigs  would 
deny  the  name  of  alkaloid  is  morphine,  the  first  substance, 
indeed,  which  received  this  name.  Further  investigation  has  shown, 
moreover,  that  of  the  basic  derivatives  of  the  same  plant  some 
may  be  derivatives  of  pyridine  and  others  not.  Finally,  the 
natural  bases  of  complicated  structure,  whose  constitution  is  not 
yet  fully  known,  appear  to  be  only  in  part  derivatives  of  pyridine. 

It  seems  necessar}',  therefore,  to  return  to  the  original  signifi- 
cance of  the  word  alkaloid  and  to  apply  it  without  distinction 
to  all  natural  organic  bases,  whatever  may  be  their  constitution. 

We  shall  then  consider  that  the  expressions  vegetable  alka- 
loids and  vegetable  bases  are  identical  in  meaning  and  that  they 
include  all  those  substances  which  are  directly  obtained  from 
the  plant  and  which  are  able  to  unite  vriih  acids  to  form  salts. 

The  history'  of  alkaloidal  chemistiy'  begins  ’^dth  the  early 
part  of  the  last  century'.  In  1803  Derosne  in  Paris  obtained 
from  opium  a cry'stalline  substance  which  he  called  opium-salt, 
and  which  must  have  been  a mixture  of  morphine  and  narcotine. 
The  basic  properties  of  this  opium-salt  he  ascribed  to  an  im- 
purity arising  from  the  alkali  used  in  the  purification. 

The  foUo’^A'ing  year  Seguin  likewise  examined  morphine, 
but  attached  no  significance  to  the  obser\'ed  alkaline  reaction 
of  his  preparation. 

The  honor  of  discovering  the  first  vegetable  base  and  of 
recognizing  its  basic  character  rests  w'ith  Sertiimer,  an  apothe- 
cary' of  Hanover.  Without  kno^'ing  of  the  work  of  Derosne 
and  Seguin,  he  in  1806  announced  that  he  had  obtained  from 
opium  a cry'stalline  body  which  was  of  basic  character,  united 
with  acids  to  form  salts,  and  in  the. opium  was  in  combination 
with  a special  acid. 


INTRODUCTION. 


3 


The  discovery  of  Sertiirner  remained  at  first  almost  unnoticed. 
It  was  at  that  time  believed  that  plants  were  able  to  produce 
only  acids,  or  bodies  of  neutral  reaction.  A second  publication 
was  required  to  attract  the  attention  of  chemists  to  this  new 
subject.  This  publication  appeared  in  1817  and  bore  the  title 
‘‘  Ueber  das  Morphium,  eine  neue  salzfahige  Grundlage  und 
die  Mekonsaure  als  Hauptbestandtheile  des  Opiums.” 

In  this  article  Sertiirner  definitely  characterizes  morphium  as 
a vegetable  alkali  and  compares  its  behavior  with  that  of  ammonia. 

These  exact  results  awakened  interest;  it  was  thought  that 
other  plants  which  possessed  marked  physiological  activity 
might  contain,  as  active  principle,  substances  analogous  to  mor- 
phium. Many  investigations  were  instituted,  with  the  result 
that  during  the  years  1817-1835  the  most  important  alkaloids 
were  isolated. 

The  following  is  a chronological  list  of  their  discovery: 


1817. 

Narcotine, 

by  Robiquet 

(( 

Emetine, 

(( 

Pelletier  and  Magendie. 

1818. 

Veratrine, 

Meissner. 

u 

Strychnine, 

u 

Pelletier  and  Caventou. 

1819. 

Brucine, 

11 

(C  il  i' 

u 

Piperine, 

(( 

Oersted. 

1820. 

Caffeine, 

C( 

Runge. 

(i 

Cinchonine 

(1 

Pelletier  and  Caventou. 

u 

Quinine, 

i( 

u a (( 

(( 

Solanine, 

IC 

Desfosses. 

1825. 

Sinapine, 

u 

Henry  and  Garot. 

1826. 

Cor)^daline, 

u 

Wackenroder. 

u 

Berberine, 

u 

Chevallier  and  Pelletan 

1828. 

Nicotine, 

({ 

Posselt  and  Reimann. 

1829. 

Aricine, 

u 

Pelletier  and  Corriol. 

(( 

Sanguinarine, 

u 

Dana. 

1830. 

Curarine, 

u 

Roulin  and  Boussingault. 

1831. 

Conine, 

(( 

Geiger. 

u 

Atropine, 

Geiger  and  Hesse. 

4 


THE  VEGETABLE  ALKALOIDS. 


1832. 

(< 

1833- 

u 

u 

{( 

1835- 


Codeine, 

Narceine, 

Quinidine, 

Aconitine, 

Colchicine, 

Hyoscyamine, 

Thebai’ne, 


by  Robiquet. 

“ Pelletier. 

“ Henr}^  and  Delondre. 

“ Geiger  and  Hesse. 

(I  u u u 

U U ((  II 

“ Pelletier  and  Thiboumery. 


The  composition  of  these  substances  was  established  by 
numerous  analyses,  the  most  of  which  we  owe  to  Liebig,  Ger- 
hardt,  Regnault,  and  Laurent. 

Since  1835  the  number  of  newly  discovered  alkaloids  has 
increased  year  by  year;  to-day  we  have  more  than  two  hundred 
vegetable  bases,  which  have  been  fully  purified,  carefully  de- 
scribed and  analyzed.  In  the  case  of  a large  number  we  have 
learned  much  regarding  the  structure  of  the  molecule,  and  in 
many  instances  have  succeeded,  indeed,  in  effecting  the  com- 
plete synthesis  of  the  base — the  best  test  of  the  accuracy  of 
our  present  conceptions  regarding  the  constitution  of  the 
alkaloids. 

The  complicated  structure  of  the  alkaloids  first  discovered 
rendered  a study  of  their  constitution  very  difficult.  Berzehus 
explained  their  basic  character  by  assuming  that  they  held 
ammonia  attached  to  an  indifferent  group — to  a hydrocarbon 
or  an  organic  oxide.  Others,  again,  supposed  that  the  nitro- 
gen was  united  with  oxygen,  or  that  it  occurred  in  a form  hke 
that  of  cyanogen. 

It  remained  for  Liebig  to  afford  the  correct  solution.  He 
considered  these  bases  as  ammonia  in  which  a hydrogen  atom 
was  replaced  by  an  organic  radical. 

The  classical  investigations  of  Wurtz  and  of  Hofmann, 
which  led  (1848)  to  the  discovery  of  the  artificial  organic  bases, 
fully  confirm  this  view.  It  was  recognized  that  the  artificial 
as  well  as  the  natural  bases  were  partly  or  completely  substituted 
ammonias.  Apphcation  to  the  alkaloids  was  now  made  of 
the  reactions,  through  which  Hofmann  had  learned  to  distinguish 


8 


THE  VEGETABLE  ALKALOIDS. 


their  structure.  Also  in  this  direction  considerable  success  has 
been  attained.  If  we  disregard  the  two  bases,  choline  and  betaine, 
which  belong  to  the  group  of  the  fatty  amines  and  whose  synthesis 
was  effected  by  Wurtz  (1857)  and  Liebreich  (1869),  and  con- 
sider only  the  alkaloids  of  cyclical  structure,  then  the  honor  rests 
with  Ladenburg  of  having  first  effected  the  complete  synthesis 
of  such  an  alkaloid;  in  1886  he  succeeded  in  building  up  from 
the  elements  conine,  the  chief  alkaloid  of  the  hemlock. 

The  same  year  Hantzsch  prepared  the  methyl-betaine  of 
nicotinic  acid,  and  this  was  shown  by  Jahns  to  be  identical  with 
trigonelline.  Since  then  still  other  alkaloids  have  been  synthe- 
sized: arecaidine  and  arecoline  by  Jahns  (1891);  piperine  by 
Ladenburg  and  Scholtz  (1894);  the  bases  of  the  xanthine  group, 
xanthine,  caffeine,  theobromine,  and  adenine  by  Fischer  (1895- 
1898);  atropine,  atropamine,  belladonine,  and  inactive  cocaine 
by  Willstatter  (1901,  1902);  and  nicotine  by  Pictet  (1903). 


This  work  is  divided  into  two  parts.  The  first  part  gives  a 
rapid  review  of  the  artificial  derivatives  oj  pyridine. 

The  chief  data  which  we  have  in  regard  to  the  constitution 
of  a large  number  of  alkaloids  rest  upon  investigations  concerning 
the  constitution  of  simple  pyridine  derivatives,  into  which  these 
alkaloids  are  converted  by  their  decomposition.  Consequently 
it  seems  to  us  best  to  discuss  first  the  structure  of  these  derivatives 
and  to  indicate  the  methods  which  have  been  employed  in  deter- 
mining their  constitution.  In  this  first  part,  however,  we  shall 
not  lose  sight  of  our  chief  object,  the  study  of  the  constitution 
of  the  vegetable  alkaloids,  and  we  shall  therefore  consider  only 
those  artificial  derivatives  which  in  their  mode  of  formation,  in 
their  molecular  structure,  or  in  any  other  important  way  are 
closely  related  to  the  natural  bases. 

In  the  second  part  we  shall  seek  to  gather  together  system- 
atically the  experimental  results  which  have  ‘ -thus  far  been 
derived  from  the  study  of  the  chemical  constitution  of  the  natural 


INTRODUCTION. 


9 


alkaloids,  and  to  discuss  the  theoretical  conclusions  which  have 
been  drawn  from  these  results.  No  attempt  will  be  made  to  present 
a complete  monograph  of  the  vegetable  alkaloids;  we  shall  not 
consider  in  detail  either  their  physiological  or  physical  properties, 
nor  shall  we  present  the  specific  tests  employed  in  detecting  the 
natural  bases.  Attention  will  be  fixed  rather  on  the  purely  chemi- 
cal behavior  of  the  alkaloids  and  the  bearing  of  this  on  their 
chemical  constitution. 


CHAPTER  XVI. 


THE  TOBACCO  ALKALOIDS. 


For  many  years  it  was  supposed  that  the  leaves  of  the  tobacco- 
plant  {Nicotiana  tabaccum  L.,  family  of  the  Solanaceae)  con- 
tained but  one  alkaloid,  nicotine.  In  1901,  however,  Pictet  and 
Rotschy  ^ showed  that  there  are  present  in  tobacco,'  as  in  most 
alkaloid-bearing  plants,  several  organic  bases. 

Thus  far  the  following  four  alkaloids  have  been  isolated: 


These  alkaloids  are  found  in  the  aqueous  extract  from  tobacco ; 
in  their  separation  advantage  may  be  taken  of  the  fact  that  the 
first  two  are  volatile  with  steam.  The  last  three  have  been 
separated  in  very  small  quantities  as  compared  with  nicotine; 
of  the  entire  alkaloidal  content  of  the  aqueous  extract,  nicoteine 
forms  possibly  2%,  nicotimine  J%,  and  nicotelline  tV%- 

In  the  plant  these  alkaloids  are  in  combination  chiefly  with 
malic  and  citric  acids,  to  a less  extent  with  oxalic,  tartaric,  and 
succinic  acids. 


Nicotine  was  isolated  from  the  leaves  of  the  tobacco-plant 
by  Posselt  and  Reimann  ^ in  1828.  The  quantity  found  in  the 


Nicotine . . . 
Nicotimine 
Nicoteine. 
Nicotelline 


I.  Nicotine. 


^ Pictet  and  Rotschy,  B.  34,  696. 

^ Posselt  and  Reimann,  Magazin  fur  Pharmacie,  24,  138. 


159 


i6o 


THE  VEGETABLE  ALKALOIDS. 


plant  varies  considerably  (0.6-8%) ; in  general  the  better  grades 
of  tobacco  contain  the  smaller  amounts  of  the  alkaloid. 

The  empirical  formula  of  nicotine,  H14N2,  was  established 
by  Melsens  ^ in  1843. 

Nicotine  is  a colorless  liquid  which  boils  without  decomposi- 
tion at  245°,  but  does  not  solidify  at-  —30°;  its  specific  gravity 
is  1. 01  at  20°.  In  the  pure  condition  it  is  almost  odorless  and 
acquires  the  odor  peculiar  to  tobacco  only  after  standing  for 
some  time  in  contact  with  the  air.  Its  taste  is  sharp  and  burning. 
It  is  very  hygroscopic  and  dissolves  readily  in  water  and  the 
ordinary  organic  solvents.  The  free  alkaloid  is  strongly  laevo- 
rotatory;  its  salts,  on  the  contrary,  are  dextrorotatory. 

Nicotine  is  one  of  the  most  active  poisons  with  which  we 
have  to  deal;  the  inhalation  of  its  vapor  even  in  small  quantities 
occasions  difficulty  in  breathing. 

It  is  a diacid  base  and  forms  salts  with  one  or  two  equivalents 
of  acid.  It  unites  with  two  molecules  of  an  alkyl  iodide.^  With 
methyl  iodide  it  forms  two  isomeric  methiodides:  the  first  is 
obtained  by  directly  mixing  equimolecular  quantities  of  the  two 
substances ; the  second  by  treating  the  monohydriodide  of  nicotine 
with  an  excess  of  methyl  iodide  and  afterwards  eliminating  the 
hydriodic  acid  by  means  of  sodium  carbonate.® 

These  results  indicate  that  nicotine  is  a bitertiary  base.  In 
apparent  contradiction  to  them,  however,  is  an  observation  of 
Etard  ® that  the  alkaloid  with  acetyl  and  benzoyl  chloride  yields 
an  acetyl  and  a benzoyl  derivative. 

But,  as  Pinner  ^ has  shown,  this  contradiction  is  only  apparent. 
If  the  acetyl-  or  benzoyl-nicotine  of  Etard  is  saponified,  nicotine 
is  not  again  obtained,  but  an  isomeric  base,  which  has  received 
the  name  metanicotine.  This  is  an  oily  liquid  which  is  optically 
inactive  and  boils  at  275-278°.  It  forms  a secondary  base;. 


^Melsens,  A.  ch.  [3]  9,  465. 

^ Kekule  and  von  Planta,  A.  87,  2.  Stahlschmidt,  A.  90,  222. 

® Pictet  and  Genequand,  Chemiker-Zeitung,  21,  246. 

« Etard,  C.  r.  97,  1218;  117,  170,  278;  Bl.  [2]  42,  297;  [3]  14,  342. 
’Pinner,  B.  27,  1053,  2861;  28,  456. 


THE  TOBACCO  ALKALOIDS. 


i6i 


treated  with  acetic  anhydride  or  benzoyl  chloride,  it  yields 
the  acetyl  or  benzoyl  derivative  from  which  it  was  obtained. 
From  this  Pinner  concludes  that  these  are  not  derivatives  of 
nicotine  itself,  but  of  metanicotine,  and  that  in  the  reaction  in 
which  they  are  formed  tertiary  nicotine  is  probably  transformed 
to  secondary  metanicotine.  We  shall  return  to  this  reaction 
later  on. 

Nicotine  is  an  unsaturated  body.  When  heated  to  260° 
with  hydriodic  acid  and  red  phosphorus  it  is  reduced  to  dihy- 
drofiicotine,  C10H16N2,  a laevorotatory  liquid  boiling  at  263-264°. 
On  treatment  with  sodium  and  alcohol  it  adds  six  or  eight  atoms 
of  hydrogen  and  yields  hexahydronicotine  and  octohydronicotine. 

Hexahydronicotine,  C10H20N2,  first  obtained  by  Liebrecht,® 
has  been  studied  chiefly  by  Blau.®  It  is  a solid  which  melts 
near  30°  and  boils  at  245^.5.  It  dissolves  readily  in  water,  alcohol, 
and  ether,  and  closely  resembles  piperidine  in  odor.  It  is  a diacid 
base  of  secondar}^-tertiar\'  character  (mononitroso-derivative). 

Octohydronicotme,  C10H22N2,  is  a liquid  which  boils  at  259- 
260°.  It  yields  with  nitrous  acid  a dinitroso-derivative  and 
it  is  consequently  a bi-secondary  base. 

On  passing  the  vapor  of  nicotine  through  a tube  heated  to 
redness,  Cahours  and  Etard  obtained  hydrogen,  ammonia, 
hydrocyanic  acid,  methane,  ethane,  ethylene,  propylene,  and 
pyridine  bases. 

Among  these  last  they  isolated  /?-propylpyridine,  a lutidine, 
a picoline,  and  pyridine.  The  presence  of  these  bases  has  also 
been  determined  in  tobacco-smoke.^^ 

Oxidation  of  Nicotine. — Nicotine  is  readily  oxidized;  on 
exposure  to  the  air  it  absorbs  oxygen,  turning  brown  in  color. 
Under  the  action  of  oxidizing  agents  it  yields  different  products 
whose  study  has  thrown  much  light  on  the  constitution  of  the 
alkaloid. 

® Liebrecht,  B.  i8,  2969;  19,  2587. 

® Blau,  B.  24,  326;  26,  628,  1029;  27,  2535;  M.  13,  330. 

Cahours  and  Etard,  C.  r.  88,  999;  90,  275;  92,  1079;  Bl.  [2]  33,  951;  34,  449. 

“ Vohl  and  Eulenberg,  A.  Pharm.  147,  130.  Kissling,  Dingier' s polytech- 
nisches  Journal,  244,  64,  234.  Le  Bon  and  Noel,  C.  r.  90,  1538. 


i62 


THE  VEGETABLE  ALKALOIDS. 


By  the  action  of  chromic  acid  on  nicotine,  Huber  in  1867 
obtained  an  acid  of  the  formula  CeHgNOj,  which  he  named 
nicotinic  acid.  Later  the  same  result  was  attained  by  Weidel 
and  Laiblin  by  using  nitric  acid  or  potassium  permanganate. 
Now  nicotinic  acid  we  found  to  be  /?- pyridine  carboxylic  acid 
(page  57);  nicotine  is  accordingly  a pyridine  derivative  having 
in  the  /^-position  the  group  — CgHjoN : 


COOH 

1 

\/ 

1 1 
\/ 

N 

N 

Nicotinic  acid 

Nicotine 

The  oxidation  of  the  quaternary  derivatives  of  nicotine  leads- 
to  a like  result.  We  have  seen  that  nicotine  yields  two  mono- 
methiodides.  One  of  these  is  formed  by  treating  the  monohy- 
driodide  of  the  alkaloid  with  methyl  iodide.  In  this  derivative,, 
then,  the  methyl  iodide  is  attached  to  that  nitrogen  atom  which 
;is  less  strongly  basic. 

On  changing  this  methiodide  to  the  hydroxide  and  oxidizing 
it  with  potassium  permanganate,  Pictet  and  Genequand  obtained 
trigonelline  (the  methyl  betaine  of  nicotinic  acid): 


/ ^-C^HioN 

0 

\/ 

\/  1 

N— OH 

1 

N 0 

1 

CH3 

I 

CH3 

Nicotine  monomethyl 
hydroxide 

Trigonelline 

This  result  seems  to  indicate  that  the  nitrogen  atom  of  the 
pyridine  nucleus  is  less  basic  than  the  other,  and  that  in  the 


Huber,  A.  141,  271;  B.  3,  849. 

13  Weidel,  A.  165,  328. 

11  Laiblin,  A.  196,  129;  B.  10,  2136;  13,  1212,  1996. 
13  Pictet  and  Genequand,  B.  30,  2117. 


THE  TOBACCO  ALKALOIDS.  163 

monacid  salts  of  the  alkaloid  the  acid  is  attached  to  the  nitrogen 
of  the  group  CgHi^N. 

With  weaker  oxidizing  agents  nicotine  yields  other  oxidation- 
products.  Heating  it  with  mercuric  oxide  to  240°  gives  rise 
to  oxy trinicotine ^ C35H27N6O2.  Hydrogen  peroxide  oxidizes  nico- 
tine to  a base,  oxynicotine  {nicotine  oxide) ^ CioHi4N20.^® 

Under  the  action  of  potassium  ferricyanide  in  alkaline  solu- 
tion, of  silver  oxide,  or  of  silver  acetate,  nicotine  loses  four  atoms 
of  hydrogen  and  is  converted  into  a base,  nicotyrine^  C10H10N2. 
Cahours  and  Etard,  who  first  obtained  this  substance,  gave  it 
the  name  is odi pyridine.  When,  however,  it  was  shown  that 
nicotine  is  not  a dipyridyl  derivative,  as  it  had  been  supposed 
to  be,  Blau  proposed  that  the  name  be  changed  to  nicotyrine. 

Nicotyrine  is  a colorless,  oily  liquid  which  boils  at  280-281°. 
It  is  little  soluble  in  water;  its  odor  is  characteristic.  Unlike 
nicotine,  nicotyrine  is  optically  inactive. 

Action  of  Bromine  on  Nicotine. — This  action  has  been  studied 
by  Pinner.  When  a solution  of  nicotine  in  acetic  acid  is  treated 
at  the  ordinary  temperature  with  bromine  there  is  formed  a 
perbromide,  CioHnBr5N20.  Boiling  water,  ammonia,  or  sul- 
phurous acid  serve  to  convert  the  latter  into  dihromcotininej 
C5H4N — C5HeBr2NO  (prisms  melting  at  125°).  On  oxidation 
dibromcotinine  yields  nicotinic  acid — a reaction  which  indi- 
cates that  the  pyridine  nucleus  of  the  molecule  has  not  been 
affected  by  the  bromine.  On  reduction  with  zinc-dust  and 
dilute  hydrochloric  acid,  it  is  converted  into  cotinine,  C10H12N2O. 
Cotinine  forms  a mass  of  radiating  crystals  which  melt  at  50°; 
it  boils  at  336°.  Both  dibromcotinine  and  cotinine  are  monacid 
bases. 

If  nicotine  is  heated  to  100°  with  bromine  in  a solution  of 
hydrobromic  acid,  it  yields  the  hydrobromide  of  dihromticoniney 
C5H4N — C5H4Br2N02-HBr.  The  free  dibromticonine  forms 

granular  cr}^stals  which  melt  at  196°.  It  is  likewise  a monacid 


Pinner  and  Wolffenstein,  B.  24,  61,  1378;  25,  1428.  Auerbach  and  Wolffen- 
stein,  B.  34,  2411. 

Pinner,  B.  25,  2807;  26,  292,  765;  27,  2861;  28,  18,  1932. 


3 0112  072534065 


164 


THE  VEGETABLE  ALKALOIDS. 


base,  and  on  oxidation  yields  nicotinic  acid.  Reduction  with 
zinc-dust  in  alkaline  solution  gives  rise  to  monobromticonme, 

C5H4N— CsH^BrNO,.  ... 

When  heated  with  baryta-water  to  100°,  dibromticonine  is 
decomposed  into  nicotinic  acid,  malonic  acid,  and  methylamine. 
This  decomposition  indicates  that  nicotine  contains  the  atomic 
groups 

-c— C— C— C—  — NCHg 


N 

Inactive  Nicotine— Nicotine  possesses  a high  specific  rotatory 
power  -i66°.33).  The  conversion  of  the  active  alkaloid 

into  the  inactive  form  is  effected  by  heating  an  aqueous  solution 
of  the  monochloride  or  sulphate  for  some  time  at  about  200  . 
Pictet  *’  thus  reduced  the  specific  rotation  to  - 3°.g5,  which  repre- 
sents a conversion  into  inactive  nicotine  to  the  extent  of  97.7%- 
In  nearly  all  its  properties,  save  optical  activity,  t-mcotme 
appears  to  be  identical  with  the  active  form.  From  this  Pictet 
concludes  that  the  former  does  not  constitute  a distinct  racemic 
derivative,  but  is  simply  a mixture  of  d-  and  f-mcotine. 

The  separation  of  f-nicotine  into  its  active  constituents  has 
been  partly  effected  recently  by  Pictet  and  Rotschy.^*  By  re- 
peatedly recrystallizing  the  salt  formed  with  <f-tartaric  acid,  a 
tartrate  is  obtained  whose  melting-point,  rotatory  power,  and 
other  properties  correspond  with  those  of  the  salt  resulting  from 
the  interaction  of  the  same  acid  and  /-nicotine.  The  /-nicotine 
derived  from  this  salt  is  in  all  respects  identical  with  the  natural 

alkaloid.  . ^ 

Constitution  of  Nicotine.-From  the  oxidation  of  nicotine  to 

nicotinic  acid  it  is  clear  that  the  alkaloid  is  a pyridine  in  which 
a /3-hydrogen  is  replaced  by  the  group  C^H^N.  It  remains 
then  to  determine  the  constitution  of  this  group. 


18  Pictet,  33,  2355. 

1®  Pictet,  work  yet  unpublished. 


